The present invention relates to a biodegradable vehicle and filler (referred to in this invention as biodegradable vehicle), which can be mixed with one or more biologically active substances (BAS), or can be used as a biodegradable filler to fill in cavities or body tissues in animals, birds and humans. The consistency and rheology, hydrophilicity and hydrophobicity, and in vivo degradation rates of the biodegradable vehicle is controlled by modulating the molecular weight of polymers and copolymers, concentration of plasticizers, ratios of two or more plasticizer in the blends, types of polymers and copolymers, copolymer ratios, and ratios of blends of polymers with different molecular weights or different copolymers. The biodegradable vehicle is mixed with one or more BAS (which is separately stored away from the biodegradable vehicle in an appropriate container) just prior to use. Mixing of the BAS with the biodegradable vehicle can be accomplished by simply stirring the mixture with a stirring device, or by triturating the mixture or employing an ointment mill or a suitable device or apparatus or equipment that can be used for blending/mixing. Alternatively, a device, which resembles two syringes, attached together with a removable partition or a valve assembly can also be used to uniformly mix the BAS with the biodegradable vehicle. The mixing is performed in order to dissolve or uniformly suspend the BAS particles in the biodegradable vehicle. Modulating the polymer to plasticizer ratio, polymer molecular weight, copolymer ratio, and hydrophobicity and hydrophilicity of the plasticizer controls the release of the BAS from the biodegradable vehicle.
Biodegradable polymers refer to those polymers and copolymers that are slowly converted to nontoxic degradation products in the body. Examples include homopolymers and copolymers of polylactic acid (PLA), polyglycolic acid, polycaprolactone (PCL), polyanhydrides, polyorthoesters, polyaminoacids, pseudopolyaminoacids, polyhydroxybutyrates, polyhydroxyvalerates, polyphophazenes, polyalkylcyanoacrylates. These polymers have been used to prepare drug delivery systems such as microspheres and microcapsules (Schindler A, Jeffcoat R, Kimmel G L, Pitt C G, Wall M E and Zwelinger R., in: Contemporary Topics in Polymer Science, Pearce E M and Schaefgen J R, eds., Vol. 2, Plenum Publishing Corporation, New York, pp. 251-289, 1977; Mason N S, Gupta D V S, Keller, D W, Youngquist R S, and Sparks R F. Biomedical applications of microencapsulation, (Lim F, ed.), CRC Press Inc., Florida, pp. 75-84, 1984; Harrigan S E, McCarthy D A, Reuning R and Thies C., Midl. Macromol. Monograph, 5:91-100, 1978.; Sanders L M, Burns R, Bitale K and Hoffinan P., Clinical performance of nafarelin controlled release injectable: influence of formulation parameters on release kinetics and duration of efficacy., Proceedings of the International Symposium on Controlled Release and Bioactive Materials, 15:62-63, 1988; Mathiowitz E, Leong K and Langer R., Macromolecular drug release from bioerodible polyanhydride microspheres, in: Proceedings of the 12th International Symposium on Controlled Release of Bioactive Materials, Peppas N and Haluska R, eds., pp. 183, 1985), films (Jackanicz T M, Nash H A, Wise D L and Gregory J B. Polylactic acid as a biodegradable carrier for contraceptive steroids., Contraception, 8:227-233, 1973.; Woodland J H R, Yolles S, Blake A B, Helrich M and Meyer F J. Long-acting delivery systems for narcotic antagonist. I. J. Med. Chem., 16:897-901, 1973), fibers (Eenink M J D, Maassen G C T, Sam A P, Geelen J A A, van Lieshout J B J M, Olijslager J, de Nijs H, and de Jager E. Development of a new long-acting contraceptive subdermal implant releasing 3-ketodesogeatrel., Proceedings of the 15th International Symposium on Controlled Release of Bioactive Materials, Controlled Release Society, Lincolnshire, Ill. pp. 402403, 1988), capsules (Sidman K R, Schwope A D, Steber W D, Rudolph S E, Paulin S B. Biodegradable, implantable sustained release systems based on glutamic acid copolymers. J. Membr. Sci., 7:277-291, 1980; Pitt C G, Gratzl M M, Jeffcoat M A, Zweidinger R and Schindler A. Sustained drug delivery systems II: Factors affecting release rates from poly-xe2x96xa1-caprolactone and related biodegradable polyesters., J. Pharm. Sci., 68(12):1534-1538, 1979), discs (Cowsar D R, Dunn R L., Biodegradable and non-biodegradable fibrous delivery systems, in: Long acting Contraceptive Delivery Systems, Zatuchni G I, Goldsmith A, Shelton J D and Sciarra J J, eds., Harper and Row, Publishers, Philadelphia, pp. 145-148, 1984), wafers (Brem et al., J. Neurosurgery, 74:441-446, 1991), and solutions (Dunn et al., U.S. Pat. No. 4,938,763; 5,324,519; 5,324,520; 5,278,201; 5,340,849; 5,368,859; 5,660849; 5,632,727; 5,599,552; 5,487,897). However, all these systems have at least one BAS, which is incorporated into the drug delivery system during the manufacture of dosage forms. Hence, these dosage forms have severe limitations in that, drug loading within a drug delivery system cannot be easily changed because the BAS is already incorporated into the drug delivery system at the time of manufacturing. Moreover, occasionally, there exists a possibility where a certain percentage of the BAS often degrades because of its exposure to the solvents, chemicals or other harsh manufacturing conditions during the preparation of the drug delivery system. Therefore, there clearly exists a need for developing a more versatile system where the BAS-loading (dose of BAS) can be tailored just prior to use, and the stability of the BAS can be enhanced.
The present invention relates to methods for preparing a biodegradable vehicle. It also describes the composition of the biodegradable vehicle and the process of blending one or more BAS with the biodegradable vehicle just prior to its use. Keeping the BAS separated from the biodegradable vehicle can enhance the stability of the BAS. Moreover, the dose of BAS (BAS-loading) can be tailored by varying the ratio of the biodegradable vehicle to the BAS. An appropriate quantity of one or more BAS, as required by the end user, is blended with the biodegradable vehicle just prior to use. Mixing of the BAS with the biodegradable vehicle can be accomplished by simply stirring the mixture with a stirring device, or by triturating the no mixture or employing an ointment mill or a suitable device or apparatus or equipment that can be used for blending/mixing. Alternatively, a device, which resembles two syringes or syringe-like devices (e.g. pumps in which materials can be mixed by depressing a trigger-like device) attached together with a removable partition or a valve assembly can also be used to uniformly mix the BAS with the biodegradable vehicle. The BAS is loaded in one syringe or compartment and the biodegradable vehicle is loaded in the other compartment. A removable partition or a valve, which will allow the contents of the two compartments to be mixed uniformly, separates the two compartments. The mixing process is performed in order to dissolve or uniformly suspend the BAS particles in the biodegradable vehicle. The biodegradable vehicles can be free-flowing or viscous liquid, gel or paste. The method of manufacturing the biodegradable vehicle described in the present invention involves dissolving one or more biodegradable polymers and one or more plasticizers in a volatile solvent or mixture of volatile solvents. The volatile solvent is then removed using vacuum or evaporated at an elevated temperature, or removed using both vacuum and elevated temperature. The biodegradable vehicle could be sterilized in the final packaging by an appropriate technique including irradiation sterilization technique. Alternatively, the biodegradable vehicle can be prepared from pre-sterilized components in an aseptic environment. Sterilization of the solvents and plasticizers used in the manufacturing process could be accomplished by an appropriate sterilization technique such as filtration, autoclaving or irradiation. The sterilized biodegradable vehicle is blended with appropriate quantities of one or more BAS just prior to its use.
Advantages of the biodegradable vehicle described in the present invention include the flexibility of tailoring the dose of the BAS in the system by blending the requisite amount of BAS and the biodegradable vehicle just prior to its use, and enhancing stability of the BAS since it is blended with the biodegradable vehicle just prior to its use. A major reason for the enhanced stability of the BAS is that the BAS is not subjected to exposure to solvents, chemicals or the harsh processing conditions during the manufacture of the biodegradable vehicle. Moreover, the BAS is stored in an appropriate separate container; hence it does not come in contact with the biodegradable vehicle until it is blended with the vehicle just prior to use.
The biodegradable vehicle without blending any BAS may be used as a tissue or cavity filler or spacer in the body, whereas the biodegradable vehicle blended with the BAS just prior to its use may be used for the treatment of a variety of diseases and pathological conditions. The final composition with or without the BAS may be injected, implanted or applied directly to tissues in animals, birds and humans.